Benzamidine derivatives and the use thereof as medicaments with LTB4-antagonistic effect

ABSTRACT

Novel benzamidines, having LTB4-antagonistic activity, of the formulamethods for their preparation, their and their use as medicaments.

RELATED APPLICATIONS

This application is filed pursuant to 35 U.S.C. 371 and claims benefit under 35 USC 120 PCT/EP97/04921 filed Sep. 9, 1997.

The present invention relates to new benzamidine derivatives, processes for preparing them and their use in pharmaceutical compositions. The new benzamidine derivatives correspond to general formula 1

wherein

A denotes —O—C₂-₄-alkylene-O— or —C₁-₃-alkylene-O—

R₁ denotes branched or unbranched C₁-₆-alkyl, branched or unbranched C₃-₆-alkenyl, preferably allyl or F, Cl, Br, I;

R₂ denotes hydrogen, branched or unbranched C₁-₆-alkyl, branched or unbranched C₃-₆-alkenyl, preferably allyl or F, Cl, Br, I;

R₃ and R₄, which may be identical or different, independently of one another denote hydrogen, branched or unbranched C₁-₆-alkyl, branched or unbranched C₃-₆-alkenyl, preferably allyl, C₁-₆-alkoxy, (C₁-₄-alkyl)OC(O)O—, OH or CF₃ or together denote a fused-on mono- or fused bi-cyclic ring system which is completely or partially conjugated and optionally contains one or two heteroatoms from the group oxygen, sulphur or nitrogen, and which may be optionally substituted by OH, C₁-₄-alkoxy or C₁-C₄-alkyl;

R₅ denotes hydrogen, aryl, preferably phenyl, —O-phenyl, —CR₇R₈-phenyl, —C(O)phenyl, —SO₂phenyl, —CH(OH)phenyl, wherein the phenyl ring may be substituted by OH, —C₁-₄-alkoxy, or it denotes —C(O)NR₉R₁₀;

R₆ denotes hydrogen, C₁-₆-alkoxycarbonyl, (C₁-₅-alkyl)-carbonyl or —C(O)—O—(C₁-₆-alkylene)-NR₁₁R₁₂;

R₇ and R₈, which may be identical or different, denote hydrogen, branched or unbranched C₁-₈-alkyl, or CF₃;

R₉ and R₁₀, which may be identical or different, independently of one another denote hydrogen, branched or unbranched C₁-₈-alkyl;

R₁₁ and R₁₂, which may be identical or different, independently of one another denote hydrogen, branched or unbranched C₁-₈-alkyl;

optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.

Preferred compounds of general formula 1 are those wherein

A denotes —OCH₂CH₂O—, —CH₂O—, —CH₂CH₂CH₂O—;

R₁ denotes branched or unbranched C₁-₅-alkyl, allyl;

R₂ denotes hydrogen;

R₃ denotes hydrogen, C₁-₆-alkyl, OCH₃, C₂H₅OC(O)O—, OH, Cl, F, CF₃;

R₄ denotes hydrogen, —OCH₃, OH;

R₃ and R₄ together denote a fused-on benzene ring, 3,4-dihydrocoumarin or 1,3-dioxolane which may be substituted by OH, C₁-C₃-alkyl or OCH₃;

R₅ denotes hydrogen, phenyl, O-phenyl, —CR₇R₈-phenyl, —SO₂phenyl, wherein the phenyl ring may be substituted by OH or OCH₃, or it denotes —C(O)NR₉R₁₀;

R₆ denotes hydrogen or C₁-₄-alkoxycarbonyl or —C(O)—O(CH₂)₂—N(C₂H₅)₂;

R₇ and R₈, which may be identical or different, independently of one another denote hydrogen, CH₃ or CF₃;

R₉ and R₁₀, which may be identical or different, denote hydrogen, branched or unbranched C₁-C₈-alkyl.

Unless specifically stated otherwise the general definitions are used as follows:

C₁-₈-alkyl, C₁-₅-alkyl and C₁-₄-alkyl generally denote a branched or unbranched hydrocarbon group having 1 to 4 or 5 or 8 carbon atoms, which may optionally be substituted with one or more halogen atoms—preferably fluorine—which may be the same as or different from each other. The following hydrocarbon groups are mentioned by way of example:

methyl,ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2,-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise specified, lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl are preferred.

Accordingly, alkylene denotes a branched or unbranched double-bonded hydrocarbon bridge having 1 to 8 carbon atoms which may optionally be substituted with one or more halogen atoms—preferably fluorine—which may be the same as or different from each other.

Aryl generally denotes an aromatic group having 6 to 10 carbon atoms—as well as in compositions, where the aromatic group may be substituted by one or more lower alkyl groups, trifluoromethyl groups, cyano groups, alkoxy groups, nitro groups, amino groups and/or one or more halogen atoms, which may be identical to or different from one another; the preferred aryl group is an optionally substituted phenyl group, whilst the preferred substituents are halogen—such as fluorine, chlorine or bromine—and hydroxyl.

Alkoxy generally denotes a straight-chained or branched hydrocarbon group having 1 to 8 carbon atoms, bound via an oxygen atom. A lower alkoxy group having 1 to 3 carbon atoms is preferred. The methoxy group is particularly preferred.

As has been found, the compounds of formula 1 are characterised by their wide range of possible applications in the therapeutic field. Particular mention should be made of those applications in which the LTB₄-receptor-antagonistic properties play a part. Examples include, in particular:

arthritis, asthma, chronic obstructive lung diseases, such as chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by nonsteroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis and multiple sclerosis.

The new compounds may also be used to treat diseases or conditions in which the passage of cells from the blood through the vascular endothelium into the tissues is of importance (such as metastasis) or diseases and conditions in which the combination of LTB₄ or another molecule (such as 12-HETE) with the LTB₄-receptor influences cell proliferation (such as chronic myeloid leukaemia).

The new compounds may also be used in combination with other active substances, e.g. those which are used for the same indications, or for example with antiallergics, secretolytics, β₂-adrenergics, inhaled steroids, antihistamines and/or PAF-antagonists. They may be administered by topical, oral, transdermal, nasal or parenteral route or by inhalation.

The activity ratios may be investigated pharmacologically and biochemically using tests such as those described in WO 93/16036, pp. 15 to 17—the contents of which are referred to herein.

The therapeutic or prophylactic dose depends not only on the potency of the individual compounds and the body weight of the patient but also on the nature and gravity of the illness. For oral administration the dose is between 10 and 500 mg, preferably between 20 and 250 mg. For inhalation the patient is given between about 0,5 and 25 mg, preferably between about 2 and 20 mg of active substance.

Inhalable solutions generally contain between about 0.5 and 5% of active substance. The new compounds may be administered in conventional preparations, e.g. as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, inhalable aerosols, ointments or suppositories.

The Examples which follow show some possible ways of formulating the preparations:

FORMULATION EXAMPLES

1. Tablets

Composition: Active substance according to invention  20 parts by weight Stearic acid  6 parts by weight Glucose 474 parts by weight

The ingredients are processed in the usual way fo form tablets weighing 500 mg. If desired the content of active substance may be increased or reduced and the quantity of glucose reduced or increased accordingly.

2. Suppositories

Composition: Active substance according to invention  100 parts by weight Lactose, powdered  45 parts by weight Cocoa butter 1555 parts by weight

The ingredients are processed in the usual way to form suppositories weighing 1.7 g.

3. Powder for Inhalation

Micronised active substance powder (compound of formula 1; particle size about. 0.5 to 7 μm) is packed into hard gelatin capsules in a quantity of 5 mg, optionally with the addition of micronised lactose. The powder is inhaled from conventional inhalers, e.g. according to DE-A 33 45 722, which is referred to herein.

The new compounds may be prepared using the following conventional methods, which are known from the prior art:

1. Reduction of an amidoxime of general formula 2

wherein R₁ to R₅ and A are as hereinbefore defined.

The reduction of the amidoxime may conveniently be carried out by catalytic hydrogenation, especially with Raney nickel in a lower alcohol, e.g. methanol.

The amidoxime of the formula 2 is conveniently dissolved in methanol with the addition of the calculated amount of the particular acid, the salt of which is the desired end product, and hydrogenated at ambient temperature under gentle pressure, e.g.at 5 bar, until the uptake of hydrogen has ceased.

2. Reaction of imidoesters of general formula 3

wherein R₁ to R₅ and A are as hereinbefore defined and R preferably denotes a lower alkyl group, with ammonia.

The reaction is conveniently carried out in an organic solvent at temperatures between about 0° C. and the boiling temperature of the reaction mixture, preferably between ambient temperature and about 100° C. or boiling temperature, if this is lower. Suitable solvents are polar solvents such as methanol, ethanol and propanols.

3. Reaction of a phenol of general formula 4

wherein R₁, R₂, R₆ are as hereinbefore defined, with a compound of formula 5

wherein A, R₃, R₄ and R₅ are as hereinbefore defined and L₁ denotes a nucleofugal leaving group such as a halogen atom or a sulphonic acid group.

The reaction is carried out in aprotic solvents such as dimethyl sulphoxide, dimethylformamide, acetonitrile or alcohols such as methanol, ethanol or propanol with the addition of a base (preferably an alkali metal or alkaline earth metal carbonate, hydroxide or hydride) at temperatures of between about 0 and 140° C. or the boiling temperature of the reaction mixture.

4. Reaction of an amidine of general formula 6

wherein R₁ to R₅ and A are as hereinbefore defined, with a compound of formula 7

L₂—R₆′  (7)

wherein R₆′ has the same meanings as R₆, with the exception of H, and L₂ denotes a nucleofugal leaving group such as a halogen atom (such as Cl or Br) or acyloxy.

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, methylene chloride, chloroform or dimethylformamide, preferably in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methylmorpholine or pyridine, which may simultaneously serve as solvents, at temperatures between −30 and 100° C., but preferably at temperatures between −10 and 80° C.

The compounds according to the invention may be prepared from compounds known from the prior art, inter alia using the methods described in the following Examples. Various other embodiments of the processes will become apparent to the skilled person from the specification. However, it is expressly pointed out that these Examples and the associated description are intended solely as an illustration and must not be regarded as limiting the invention.

Amidoxime: X═C(═NOH)NH₂

5.3 g of the nitrile of the above formula (X═CN) is refluxed together with 98 ml of ethanol, 3.65 g of hydroxylamine x HCl, 2.9 g of Na₂CO₃ and 21 ml of water for 5 hours. Then the mixture is distilled to dryness and the residue is stirred with water and suction filtered. 5.7 g are suspended in 25 ml of acetonitrile and mixed with 0.85 ml of methanesulphonic acid, heated and cooled again.

After suction filtering 6.4 g of the methanesulphonate are obtained in the form of white crystals.

Amidine: X═C(═NH)—NH₂

6.4 g of the amidoxime (X═C(═NOH)—NH₂) in the form of the methanesulphonate are dissolved in 100 ml of methanol and hydrogenated, using Raney nickel as catalyst, under normal conditions, until 100% hydrogen uptake has occurred. After suction filtering, the filtrate is evaporated down and the residue is recrystalled from methanol. Yield: 3.8 g of the amidine compound as the methanesulphonate. Mp. 228-30° C.

Ethoxycarbonylamidine: X═C(NCOOC₂H₅)—NH₂

2.6 g of the amidine methanesulphonate (X═C(═NH)—NH₂) are suspended with 1.6 ml of triethylamine in 50 ml of ethyl acetate and 0.6 ml of ethyl chloroformate in 5.5 ml of ethyl acetate is added thereto at ambient temperature over about 15 minutes. The reaction mixture is then washed three times with water, dried with Na₂SO₄ and evaporated down. After recrystallisation from acetonitrile the ethoxycarbonylamidine compound is obtained, mp. 142-144° C.

Following these procedures, the following compounds are obtained, for example:

No. compound salt form Mp. [° C.]  1

methane sulphonate 221-223  2

methane sulphonate 212-213  3

methane sulphonate 219-222  4

methane sulphonate >230  5

methane sulphonate 185-188  6

methane sulphonate 228-230  7

methane sulphonate  8

methane sulphonate 211-213  9

methane sulphonate 206-208 10

methane sulphonate 201-203 11

methane sulphonate 207-211 12

methane sulphonate 212-214 13

methane sulphonate 225-227 14

15

16

17

methane sulphonate 188-190 18

19

methane sulphonate >230° 20

21

22

23

24

25

26

methane sulphonate 188-190 27

methane sulphonate 216-219 28

methane sulphonate 219-222 29

methane sulphonate 176 30

methane sulphonate 212-213 31

methane sulphonate 196-200 32

158-160 33

methane sulphonate 221-223 34

methane sulphonate 230 35

methane sulphonate 185-188 36

methane sulphonate 228-230 37

methane sulphonate 233-234 38

methane sulphonate 211-213 39

methane sulphonate 201-203 40

methane sulphonate 212-214 41

methane sulphonate 230 42

methane sulphonate 206-208 43

84-86 44

methane sulphonate 225-227 45

methane sulphonate 207-211 46

142-144 47

methane sulphonate 215-221 48

methane sulphonate 209-211 49

methane sulphonate >230 50

methane sulphonate >230 51

methane sulphonate >230 52

methane sulphonate 198-200 53

methane sulphonate 218-222 54

144-147 55

methane sulphonate 185-191 56

dichloride 150-154 57

methane sulphonate 220 58

di-methane sulphonate 198-202 59

chloride 302 60

methane sulphonate 158 61

methane sulphonate 151 62

chloride 170-175 63

methane sulphonate 135-142 64

chloride 178 65

chloride 138-145 66

chloride 209-210 67

chloride 182-183 68

chloride 211-216 69

methane sulphonate 168-175 70

methane sulphonate 170-174 71

chloride 159-161 72

chloride 171-175 73

chloride 180-188 74

chloride 126-129 75

methane sulphonate 158-166 76

methane sulphonate 175-183 77

methane sulphonate 

What is claimed is:
 1. A compound of the formula 1

wherein: A is —O—C₂-₄-alkyleneO— or —C₁-₃-alkyleneO—; R₁ is branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₂ is hydrogen, branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₃ and R₄ are, independently of one another, hydrogen, branched or unnbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, C₁-₆-alkoxy, (C₁₋₄-alkyl)OC(O)O—, OH or CF₃, or R₃ and R₄ together denote a fused mono- or bicyclic ring system which is completely or partially conjugated and optionally has one or two heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen, and which is optionally substituted by OH, C₁-C₄-alkoxy or C₁-C₄-alkyl; R₅ is hydrogen, phenyl, —O-phenyl, —CR₇R₈-phenyl, —C(O)phenyl or —CH(OH)phenyl, wherein each of the foregoing phenyl moieties is optionally substituted by OH, C₁-₄-alkoxy, or —C(O)NR₉R₁₀; R₆ is hydrogen, C₁-₆-alkoxycarbonyl, (C₁₋₅-alkyl)-carbonyl or —C(O)—O—(C₁-₆-alkylene)-NR₁₁R₁₂; R₇ and R₈ are, independently of one another, hydrogen, branched or unnbranched C₁-₈-alkyl, or CF₃; R₉ and R₁₀ are, independently of one another, hydrogen or branched or unnbranched C₁-₈-alkyl; and, R₁₁ and R₁₂ are, independently of one another, hydrogen or branched or unbranched C₁-₈-alkyl; or a pharmaceutically acceptable salt thereof.
 2. A compound of the formula 1, in accordance with claim 1, wherein: A is —OCH₂CH₂O—, —CH₂O— or —CH₂CH₂CH₂O—; R₁ is branched or unnbranched C₁-₅-alkyl or allyl; R₂ is hydrogen; R₃ is hydrogen, C₁-₆-alkyl, OCH₃, C₂H₅OC(O)O—, OH, Cl, F or CF₃; R₄ is hydrogen, —OCH₃ or OH; or, R₃ and R₄ together form a fused moiety which is a benzene ring, 3,4-dihydrocoumarin system or 1,3-dioxolane system, which fused moiety is optionally substituted by OH, C₁-₃-alkyl or OCH₃; R₅ is hydrogen, phenyl, —O-phenyl, —CR₇R₈-phenyl, wherein the foregoing phenyl moities are optionally substituted by OH or OCH₃, or R₅ is —C(O)NR₉R₁₀; R₆ is hydrogen, C₁-₄-alkoxycarbonyl or —C(O)—O—(CH₂)₂—N(C₂H₅)₂; R₇ and R₈ are, independently of one another, hydrogen, CH₃ or CF₃; and, R₉ and R₁₀ are, independently of one another, hydrogen or branched or unbranched C₁-₈-alkyl; or a pharmaceutically acceptable salt thereof.
 3. A compound of the formula 2

wherein: A is —O—C₂-₄-alkyleneO— or —C₁-₃-alkyleneO—; R₁ is branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₂ is hydrogen, branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₃ and R₄ are, independently of one another, hydrogen, branched or unnbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, C₁-₆-alkoxy, (C₁₋₄-alkyl)OC(O)O—, OH or CF₃, or R₃ and R₄ together denote a fused mono- or bicyclic ring system which is completely or partially conjugated and optionally has one or two heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen, and which is optionally substituted by OH, C₁-₄-alkoxy or C₁-C₄-alkyl; and, R₅ is hydrogen, phenyl, —O-phenyl, —CR₇R₈-phenyl, —C(O)phenyl or —CH(OH)phenyl, wherein each of the foregoing phenyl moieties is optionally substituted by OH, C₁-₄-alkoxy, or —C(O)NR₉R₁₀.
 4. A process for making a compound of the formula 1

wherein: A is —O—C₂-₄-alkyleneO— or —C₁-₃-alkyleneO—; R₁ is branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₂ is hydrogen, branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₃ and R₄ are, independently of one another, hydrogen, branched or unnbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, C₁-₆-alkoxy, (C₁-₄-alkyl)OC(O)O—, OH or CF₃, or R₃ and R₄ together denote a fused mono- or bicyclic ring system which is completely or partially conjugated and optionally has one or two heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen, and which is optionally substituted by OH, C₁-C₄-alkoxy or C₁-C₄-alkyl; R₅ is hydrogen, phenyl, —O-phenyl, —CR₇R₈phenyl, —C(O)phenyl or —CH(OH)phenyl, wherein each of the foregoing phenyl moieties is optionally substituted by OH, C₁-₄-alkoxy, or —C(O)NR₉R₁₀; R₆ is hydrogen, C₁-₆-alkoxycarbonyl, (C₁₋₅-alkyl)-carbonyl or —C(O)—O—(C₁-₆-alkylene)—NR₁₁R₁₂; R₇ and R₈ are, independently of one another, hydrogen, branched or unnbranched C₁-₈-alkyl, or CF₃; R₉ and R₁₀ are, independently of one another, hydrogen or branched or unnbranched C₁-₈-alkyl; and, R₁₁ and R₁₂ are, independently of one another, hydrogen or branched or unbranched C₁-₈-alkyl; which process comprises reducing a compound of the formula 2

 wherein A and R₁, R₂, R₃, R₄ and R₅ are as previously defined in this claim.
 5. A process for making a compound of the formula 1

wherein: A is —O—C₂-₄-alkyleneO— or —C₁-₃-alkyleneO—; R₁ is branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₂ is hydrogen, branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₃ and R₄ are, independently of one another, hydrogen, branched or unnbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, C₁-₆-alkoxy, (C₁₋₄-alkyl)OC(O)O—, OH or CF₃, or R₃ and R₄ together denote a fused mono- or bicyclic ring system which is completely or partially conjugated and optionally has one or two heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen, and which is optionally substituted by OH, C₁-C₄-alkoxy or C₁-C₄-alkyl; R₅ is hydrogen, phenyl, —O-phenyl, —CR₇R₈-phenyl, —C(O)phenyl or —CH(OH)phenyl, wherein each of the foregoing phenyl moieties is optionally substituted by OH, C₁-₄-alkoxy, or —C(O)NR₉R₁₀; R₆ is hydrogen, C₁-₆-alkoxycarbonyl, (C₁₋₅-alkyl)-carbonyl or —C(O)—O—(C₁-₆-alkylene)—NR₁₁R₁₂; R₇ and R₈ are, independently of one another, hydrogen, branched or unnbranched C₁-₈-alkyl, or CF₃; R₉ and R₁₀ are, independently of one another, hydrogen or branched or unnbranched C₁-₈-alkyl; and, R₁₁ and R₁₂ are, independently of one another, hydrogen or branched or unbranched C₁-₈-alkyl; which process comprises reacting a compound of the formula 3

 wherein A and R₁, R₂, R₃, R₄ and R₅ are as previously defined in this claim with ammonia.
 6. A process for making a compound of the formula 1

wherein: A is —O—C₂-₄-alkyleneO— or —C₁-₃-alkyleneO—; R₁ is branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₂ is hydrogen, branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₃ and R₄ are, independently of one another, hydrogen, branched or unnbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, C₁-₆-alkoxy, (C₁₋₄-alkyl)OC(O)O—, OH or CF₃, or R₃ and R₄ together denote a fused mono- or bicyclic ring system which is completely or partially conjugated and optionally has one or two heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen, and which is optionally substituted by OH, C₁-C₄-alkoxy or C₁-C₄-alkyl; R₅ is hydrogen, phenyl, —O-phenyl, —CR₇R₈-phenyl, —C(O)phenyl or —CH(OH)phenyl, wherein each of the foregoing phenyl moieties is optionally substituted by OH, C₁-₄-alkoxy, or —C(O)NR₉R₁₀; R₆ is hydrogen, C₁-₆-alkoxycarbonyl, (C₁₋₅-alkyl)-carbonyl or —C(O)—O—(C₁-₆-alkylene)—NR₁₁R₁₂; R₇ and R₈ are, independently of one another, hydrogen, branched or unnbranched C₁-₈-alkyl, or CF₃; R₉ and R₁₀ are, independently of one another, hydrogen or branched or unnbranched C₁-₈-alkyl; and, R₁₁ and R₁₂ are, independently of one another, hydrogen or branched or unbranched C₁-₈-alkyl; which process comprises reacting a compound of the formula 4

 wherein R₁, R₂ and R₆ are as previously defined in this claim with a compound of the formula 5

 wherein A and R₃, R₄ and R₅ are as previously defined in this claim and L₁ is a nucleofugal leaving group, in an aprotic solvent.
 7. A process for making a compound of the formula 1

wherein: A is —O—C₂-₄-alkyleneO— or —C₁-₃-alkyleneO—; R₁ is branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₂ is hydrogen, branched or unbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, F, Cl, Br or I; R₃ and R₄ are, independently of one another, hydrogen, branched or unnbranched C₁-₆-alkyl, branched or unbranched C₃₋₆-alkenyl, C₁-₆-alkoxy, (C₁₋₄-alkyl)OC(O)O—, OH or CF₃, or R₃ and R₄ together denote a fused mono- or bicyclic ring system which is completely or partially conjugated and optionally has one or two heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen, and which is optionally substituted by OH, C₁-C₄-alkoxy or C₁-C₄-alkyl; R₅ is hydrogen, phenyl, —O-phenyl, —CR₇R₈-phenyl, —C(O)phenyl or —CH(OH)phenyl, wherein each of the foregoing phenyl moieties is optionally substituted by OH, C₁-₄-alkoxy, or —C(O)NR₉R₁₀; R₆ is hydrogen, C₁-₆-alkoxycarbonyl, (C₁₋₅-alkyl)-carbonyl or —C(O)—O—(C₁-₆-alkylene)—NR₁₁R₁₂; R₇ and R₈ are, independently of one another, hydrogen, branched or unnbranched C₁-₈-alkyl, or CF₃; R₉ and R₁₀ are, independently of one another, hydrogen or branched or unnbranched C₁-₈-alkyl; and, R₁₁ and R₁₂ are, independently of one another, hydrogen or branched or unbranched C₁-₈-alkyl; which process comprises reacting a compound of the formula 6

 wherein A, R₁, R₂, R₃, R₄ and R₅ are as previously defined in this claim with a compound of the formula 7 L₂—R₆′  (7)  wherein R₆′ is C₁-C₆-alkoxycarbonyl or C₁-C₆-acyl and L₂ is a nucleofugal leaving group.
 8. A pharmaceutical composition comprising a compound of the formula 1, in accordance with claims 1 or 2, and a pharmaceutically acceptable carrier.
 9. A method for treating arthritis, asthma, chronic obstruct lung disease, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by nonsteroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis or multiple sclerosis which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula 1, in accordance with claims 1 or
 2. 